Occupancy of the dopamine (DA) D2 receptor subtype predicts the clinical efficacy of antipsychotic medications. This finding cemented the DA hypothesis. It has been augmented by years of accumulating evidence that DA influences stimulus-response-reward pathways and that, in psychosis, at least one problem is that excessive presynaptic DA synthesis and release leads to neutral cues becoming abnormally salient.
Activity at receptors other than D2 may modulate the efficacy of different antipsychotic agents against different kinds of schizophrenia symptoms, and exacerbate or lighten the burden of adverse events. Throughout, though, the D2 receptor has remained the primary player. Even the D1, D3 and D4 subtypes have had minimal share of the action. But must this always be the case? Professor Shitij Kapur (Institute of Psychiatry, King’s College, London, UK) asked during the final education session of the Amsterdam meeting. Is there life beyond dopamine?
The broad answer: new life forms have struggled to emerge from the neurochemical swamp -- but none so far has grown to full maturity.
This has not been for lack of effort. In recent years, of 110 or so agents in development for psychiatric disorders, thirty have been for schizophrenia. Half are still in phase I. But several have progressed to large, late-stage clinical trials and then fallen at the final hurdle. These include drugs that have tried to replicate the effect of D2 receptor blockade but through a different mechanism. One approach has been via inhibition of phosphodiesterase 10 (the PDE10 inhibitors). Another attempt has been to exploit the alpha2 adrenoceptor.
A second strand of development has focused on the idea that the DA receptor can be bypassed altogether. This has led to the development of mGlutamate II/III agents to treat psychosis and – with the hope of targeting negative symptoms and cognitive deficits -- we have had Glycine transporter-1 inhibitors and the alpha7 nicotinic receptor agonists to modulate the nicotinic cholinergic system.
All of these ideas are logical and all showed promise in early studies. Targeting the second messenger PDE10, for example, makes perfect sense; and animal studies suggested an antipsychotic effect. As an add-on therapy for D2 agents, there is nothing more logical than an agent acting via glutamate. Yet – despite promising clinical evidence from phase II studies – the general picture has been one of failure in pivotal randomised studies. An exception to this is the 5HT2 blocker approach to psychosis associated specifically with Parkinson’s Disease. But whether this success will cross over to schizophrenia is unknown.
Despite these setbacks, 61% of the audience thought that there was life after dopamine. Asked when we can expect the next major breakthrough in the pharmacology of schizophrenia, only 10% said “Not in my lifetime”. Half thought it likely in 5-10 years. Professor Kapur agreed that this was a realistic hope.
Heteroreceptor complexes: unpicking their complexity
Professor Kjell Fuxe (Karolinska Institute, Stockholm, Sweden), has made an unmatched contribution to half a century of advance in our understanding of neurons, where they project to, and the intricate networks that they form. Speaking earlier in this educational session, he described different kinds of D2 heteroreceptor complexes in the ventral striatum which modulate brain circuits to the prefrontal cortex and occur at important places along the pathway.
They offer interesting potential targets for treatment of schizophrenia, he suggested. Our understanding of these complexes is at an early stage, but it is likely that pharmacological tools will be developed that influence mood and behaviour by adjusting the balance between heteroreceptors and homoreceptors and receptor-receptor interactions in D2 heteroreceptors.
A potentially important insight is that hallucinogens increase D2 receptor signalling in the D2R-5HT2A heterodimer complexes. There is also interest in D2R-oxytocin receptor complexes. The social attachment hormone oxytocin may be a naturally occurring antipsychotic, with dysfunction or disruption of this complex implicated in the disturbed emotional and social aspects of schizophrenia.
If he had to choose one of the four types of D2 heteroreceptor complexes discussed (the others involved neurotensin and A2A) Professor Fuxe would put money into the development of agents that influenced oxytocin-D2 interactions. In creating molecules that are sufficiently specific for the different types of receptor complex, though, medicinal chemists can expect busy times ahead.
